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The chemical components of the e-liquids and aerosols contained in electronic nicotine delivery systems (ENDSs), better known as vapes, were evaluated. The analytical technique used was gas chromatography-mass spectrometry, where the extraction and injection methods were established in this study. The work consisted of the analysis of twenty samples of disposable electronic cigarettes prefilled with new e-liquid, of a known brand, flavor, volume, and, in some of them, the percentage of nicotine and the number of puffs per device were indicated on the label. We detected the presence of many substances (at a qualitative and semi-quantitative level), and we achieved the quantification of benzene, toluene, and xylenes (BTX), dangerous substances that cause severe damage to health. Several of the e-liquids and aerosols present BTX concentrations above the permissible exposure limit (PEL), recommended by the Occupational Safety and Health Administration (OSHA): benzene in aerosol samples 80% > PEL, and toluene in aerosol samples 45% > PEL. The number of chemical compounds found in the samples increases from 13 to 167, the average being 52 compounds for the water extraction method, 42 compounds for the methanol extraction method of e-liquids, and 107 compounds for the direct aerosol analysis. It is a fact that many of those compounds, especially BTX, can cause serious effects on human health, affecting the respiratory, digestive, cardiovascular, pulmonary, and immune systems, as well as the brain. Therefore, the use of these devices should be considered with caution, since the substances and their chemical nature may pose significant health risks to both users and those exposed to secondhand emissions.

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating outpatient monitoring safety and efficacy following liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. Primary end point was incidence of grade ≥3 cytokine release syndrome (CRS), neurological events (NE), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient-monitored, 70%; inpatient-monitored, 30%). Median (range) follow-up was 10.6 months (1.0‒24.5). In outpatients and inpatients, respectively, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%. Among outpatients, 25% were never hospitalized after infusion and 32% were hospitalized ≤72 hours after the day of infusion; median (range) time to hospitalization was 5.0 days (2‒310). Median (range) initial hospitalization duration after liso-cel was 6.0 days (1‒28) for outpatients and 15.0 days (3‒31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and median duration of response was 14.75 months (95% confidence interval, 5.0‒not reached). OUTREACH is the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support feasibility of liso-cel administration at community sites with outpatient monitoring. ClinicalTrials.gov: #NCT03744676., (Copyright © 2024 American Society of Hematology.)

Background: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized racial and ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both., Methods: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment., Results: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR = 0.64, 95% CI = 0.45 to 0.90) and reduced post-access enrollment for HW (aOR = 0.54, 95% CI =0.34 to 0.86) and NHB (aOR = 0.60, 95% CI = 0.39 to 0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained., Conclusions: A substantial proportion of racial and ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Malignant cells are known to evade immune surveillance by engaging immune checkpoints which are negative regulators of the immune system. By restoring the T-lymphocyte mediated anti-tumor effect, immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors but have met rather modest success in hematological malignancies. Currently, the only FDA approved indications for ICI therapy are in classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials have assessed ICI therapy alone and in combination with standard of care treatments in other lymphomas, plasma cell neoplasms and myeloid neoplasms but were noted to have limited efficacy. These trials mostly focused on PD-1/PDL-1 and CTLA-4 inhibitors. Recently, there has been an effort to target other T-lymphocyte checkpoints like LAG-3, TIM-3, TIGIT along with improving strategies of PD-1/PDL-1 and CTLA-4 inhibition. Drugs targeting the macrophage checkpoint, CD47, are also being tested. Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies., Competing Interests: JV reports consulting scientific review committee with NexImmune, stock holding with NexImmume and speaker bureau with Kite/Gilead. JR reports consulting for Parexel, Bioclinica , Attivare. Serves on DSMB for Karyopharm. Advisory board for Jansenn Research funding from BMS, Sanofi and Pfizer. In addition, JR has a patent for PCT/US2021059199 pending. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor SP declared a shared affiliation with the authors PP & JR at the time of review., (Copyright © 2024 Pophali, Varela and Rosenblatt.)

Diffuse large B cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma. Although outcomes to frontline therapy are encouraging, patients who are refractory to or in relapse after first-line therapy experience inferior outcomes. A significant proportion of patients treated with additional lines of cytotoxic chemotherapy ultimately succumb to their disease, as established in the SCHOLAR-1 study. Chimeric antigen receptor (CAR) T cell therapy is a novel approach to cancer management that reprograms a patient's own T cells to better target and eliminate cancer cells. It was initially approved by the US Food and Drug Administration for patients with relapsed/refractory (r/r) DLBCL as a third line of treatment. Based on recently published randomized data, CAR-T therapy (axicabtagene ciloleucel and lisocabtagene maraleucel) also has been approved as a second line of treatment for patients who are primary refractory or relapse within 12 months of first-line therapy. Despite the proven efficacy in treating r/r DLBCL with CD19-directed CAR-T therapy, several barriers may prevent eligible patients from receiving treatment. Barriers to CAR-T therapy include cost of therapy, patient hesitancy, required travel to academic treatment centers, nonreferrals, poor understanding of CAR-T therapy, lack of caregiver support, knowledge of available resources, and timely patient selection by referring oncologists. In this review, we provide an overview of the FDA-approved CD19-directed CAR-T cell therapies (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) from pivotal clinical trials and supporting real-world evidence from retrospective studies. In both clinical trials and real-world settings, CAR-T therapy has been shown to be safe and efficacious for treating patients with r/r DLBCL: however, several barriers prevent eligible patients from accessing these therapies. Barriers to referrals for CAR-T therapy are described, along with recommendations to improve collaboration between community oncologists and physicians from CAR-T therapy treatment centers and subsequent long-term care of patients in community treatment centers., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background/objective: Cryopreservation of grafts is not common practice in allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, our center had to use cryopreserved cells for allogeneic HSCT during the COVID-19 pandemic to avoid delays in transplantation due to uncertainty regarding patient and donor exposures., Study Design: We retrospectively evaluated post-transplant engraftment and survival outcomes of adult patients who received cryopreserved versus fresh allografts during the COVID-19 pandemic., Results: Fifty-five patients with hematologic malignancies received either cryopreserved (n = 34) or fresh (n = 21) allogeneic HSCT using peripheral blood stem cells between January 2020 and December 2020. At a median follow-up time of 15 months, cryopreserved allograft recipients had significantly lower overall survival (OS) (p = 0.02). They also experienced significantly delayed neutrophil (p = 0.01) and platelet engraftments (p < 0.0001), as well as higher red blood cell transfusion-dependence after day + 60 (67.6% vs. 28.6%; p = 0.01). Significantly more cryopreserved allograft recipients received donor lymphocyte infusion than fresh allograft recipients (35.3% vs. 4.8%, p = 0.01). Neither relapse-free survival nor non-relapse mortality differed significantly between the two groups., Conclusion: Cryopreservation of allografts in combination with post-transplant cyclophosphamide may negatively affect engraftment and OS outcomes in HSCT recipients., (© 2022. Japanese Society of Hematology.)

Conditioning intensity contributes significantly to outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated two myeloablative conditioning dosing ranges of intravenous (IV) busulfan (Bu) in combination with fludarabine in 70 patients. In 2015, our practice changed to target busulfan area under the curve (AUC) of ≥ 19.7 mg*h/L. We assessed responses in patients receiving busulfan AUCs of < 19.7 mg*h/L (Low-Bu) and ≥ 19.7 mg*h/L (High-Bu). At 18-month median follow-up, no differences in overall survival (OS) and relapse-free survival (RFS) were found between Low-Bu and High-Bu groups (p = 0.35 and p = 0.29, respectively). Relapses occurred in 25.7% of patients. No differences in median time to relapse were noted. Minimal residual disease (MRD)-positive patients had a shorter median OS and RFS than MRD-negative patients. No differences were found in OS and RFS between Low-Bu and High-Bu groups in MRD-positive patients (p = 0.86 and p = 0.83, respectively), or MRD-negative patients (p = 0.56 and p = 0.38, respectively). Non-relapsed mortality (NRM) at 100 days was 3.4% vs. 4.1% in the Low-Bu vs. High-Bu groups. There were no significant differences in the incidence of acute-graft-versus-host disease (aGVHD) (71.4% vs. 63.4%) or chronic GVHD (cGVHD) (48.3% vs. 43.9%) between the groups. The cumulative incidence of grades III-IV aGVHD was 24.1% in Low-Bu group and 22.4% in High-Bu group. In conclusion, targeting a busulfan AUC of > 19.7 mg*h/L with fludarabine does not appear to add an advantage in OS and RFS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Home hemodialysis (HHD) with low-flow dialysate devices has gained popularity in recent years due to its simple design, portability, and ability to provide greater freedom of movement for our patients. However, there are doubts about the adequacy that this technology offers, since it uses monitors with low-flow bath and lactate. The aim of this study was to demonstrate the clinical benefits of low-flow HHD with the NxStage System One® recently introduced in Spain. We present the results of an observational, retrospective cohort study that included the first patients who started short daily HHD with this device in 12 Spanish centers. We analyzed the evolution of 86 patients at 0, 6 and 12 months, including data related to prescription, and evolution of biochemical parameters related to dialysis dose, anemia, mineral-bone metabolism; evolution of residual renal function, medication usage, and causes of withdrawal during the followup. We were able to demonstrate that this NxStage System One® monitor, in patients with HHD, have provided an adequate dialysis dose, with optimal ultrafiltration rate, with improvement of main biochemical markers of dialysis adequacy. The usage of this technique was associated to a decrease of antihypertensive drugs, phosphate binders and erythropoietin agents, with very good results both patient and technique survival. The simplicity of the technique, together with its good clinical outcomes, should facilitate the growth and utilization of HHD, both in incident and prevalent patients., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

AML with myelodysplasia-related changes (AML-MRC) is a subtype of AML known to have adverse prognosis. The karyotype abnormalities in AML-MRC have been well established; however, relatively little has been known about the role of gene mutation profiles by next generation sequencing. 177 AML patients (72 AML-MRC and 105 non-MRC AML) were analyzed by NGS panel covering 53 AML related genes. AML-MRC showed statistically significantly higher frequency of TP53 mutation, but lower frequencies of mutations in NPM1, FLT3-ITD Low , FLT3-ITD High , FLT3-TKD, NRAS, and PTPN11 than non-MRC AML. Supervised tree-based classification models including Decision tree, Random forest, and XGboost, and logistic regression were used to evaluate if the mutation profiles could be used to aid the diagnosis of AML-MRC. All methods showed good accuracy in differentiating AML-MRC from non-MRC AML with AUC (area under curve) of ROC ranging from 0.69 to 0.78. Additionally, logistic regression indicated 3 independent factors (age and mutations of TP53 and FLT3) could aid the diagnosis AML-MRC. Using weighted factors, a AML-MRC risk scoring equation was established for potential application in clinical setting: +1x(Age ≥ 65) + 3 x (TP53 mutation) - 2 x (FLT3 mutation). Using a cutoff score of 0, the accuracy of the risk score was 0.76 with sensitivity of 0.77 and specificity of 0.75 for predicting the diagnosis of AML-MRC. Further studies with larger sample sizes are warranted to further evaluate the potential of using gene mutation profiles to aid the diagnosis of AML-MRC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The ideal conditioning intensity in allogeneic hematopoietic stem cell transplantation (HSCT) is evolving. Previous prospective studies comparing myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) regimens in adults with acute myelogenous leukemia (AML) have shown mixed results. In many of these studies, patients were not stratified based on measurable residual disease (MRD). We evaluated the effect of conditioning intensity on the outcomes of AML patients in complete remission (CR) with flow cytometry evidence of MRD negativity. A total of 135 patients age 20 to 75 years with AML in CR1 or CR2 and flow cytometry evidence of MRD negativity who underwent allogeneic HSCT at our center between 2011 and 2019 were evaluated. We compared overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD) in recipients of MAC (n = 89) and RIC (n = 46). Although the patients receiving RIC were older (62 versus 51 years; P < .0001), there were no statistically significant differences between the groups in terms of Eastern Cooperative Oncology Group and European Leukemia Network risk criteria and disease status (CR1 or CR2) at the time of transplantation. At a median follow-up of 24.6 months, no statistically significant differences in OS (hazard ratio [HR], 0.78; 95% confidence interval [CI] 0.42 to 1.42, P = .411) or RFS (HR, 1.004; 95% CI, 0.48 to 2.09, P = .99) were identified. The cumulative incidence of NRM (HR, 0.595; 95% CI, 0.24 to 1.48; P = .2644) and relapse (HR, 1.007; 95% CI, 0.45 to 2.23; P = .9872) was not different between the 2 groups. Grade II-IV and grade III-IV acute GVHD were more frequent in the MAC group (39.3% verses 19.9% [P = .018] and 19.3% versus 2.3% [P < .001], respectively), as was moderate/severe chronic GVHD (23.6% versus 15.8%; P = .038). Our data indicate that conditioning intensity did not appear to affect OS, RFS, NRM, and relapse risk in patients with MRD-negative AML as measured by flow cytometry. RIC resulted in less severe acute and chronic GVHD., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Infections in adult patients with hematological malignancies (HM) and stem cell transplant (SCT) recipients are a significant cause of morbidity and mortality. A timely diagnosis of infections can have a major impact on outcomes. Tools that help rule out infectious causes of fever can decrease antibiotic use, toxicities, hospitalization costs, and potentially decrease antibiotic resistance in the long term. We retrospectively evaluated the ability of cell-free DNA next-generation sequencing (NGS) testing in the timely identification of pathogenic microorganisms and its impact on the antimicrobial management of immunocompromised patients with hematologic malignancies. In the period between 2018 to 2020, 95 samples were reviewed, of which 31 adult patients (32 tests) had hematologic malignancies or were recipients of SCT. The NGS tests were performed in the following patients: (a) patients with prolonged fever and negative conventional tests, (b) persistent fever despite positive conventional test and appropriate antimicrobials, and (c) fever-free patients with imaging suspicious for infection. The median time from fever to NGS sampling was 5 days (range, 1-28). The median time to NGS results was 2 days (range, 1-6). The NGS resulted in an escalation of antibiotics in 28% of cases (9/32) and de-escalation of antibiotics in 31% of cases (10/32). Overall, NGS testing changed management in nearly 59% (19/32) of patients. The sensitivity and specificity of NGS to detect clinically significant infection was 80% and 58%, respectively. The test identified uncommon and difficult to diagnose organisms such as Nocardia, Legionella, Toxoplasma and Pneumocystis jirovecii resulting in rapid antimicrobial interventions. In conclusion, in patients with HM or SCT recipients, microbial cell-free DNA sequencing allowed rapid and actionable treatment. This strategy can target appropriate antibiotic use, avoid overtreatment, and potentially decrease the hospital length-of-stay., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The 2017 ELN risk stratification has been widely adopted, but some studies have suggested the outcomes are heterogenous within the ELN risk groups and may be affected by other co-existing genetic mutations. This study evaluated the impact of DNA methylation regulatory gene ( TET2 , IDH1/2 , DNMT3A , SETBP1 ) mutations (DMRGM) evaluated by NGS in the outcome of AML patients in each ELN risk group. A total of 114 patients were analyzed with a median follow-up of 12 months. Overall, 30.7% (35/114) of patients had DMRGM. DMRGM status had no impact on CR rate in each ELN risk group. The OS, however, was significantly shorter in patients with DMRGM compared to those without DMRGM (median OS: 12 vs. 33 months, p = 0.0053). Multivariate analysis showed DMRGM status was an independent unfavorable factor for OS (HR: 2.704, 95% CI: 1.451-5.041, p = 0.0017). The adverse OS impact of DMRGM was only observed in the ELN favorable group (7 months vs. not reached, p = 0.0001), but not in the intermediate or adverse group. Among the favorable group with DMRGM (n = 16), DMRGM occurred predominantly in cases with mutated NPM1 (15/16, or 93.8%). Our results suggest that DMRGM adversely impact the outcomes of ELN favorable group patients, particularly those with mutated NPM1 . Further studies are warranted to confirm our observations.

Azacitidine (AZA) maintenance following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may reduce relapse risk and improve survival. Given logistic and toxicity-related challenges, identifying subgroups appropriate for this approach is an unmet need. Using data from two centers, we retrospectively compared event-free survival (EFS) and overall survival (OS) of AML and MDS patients who received AZA maintenance ( n  = 59) with historic controls ( n  = 90). Controls were selected according to the following criteria: no death, relapse, or Grade III-IV acute GVHD for 100 days after transplant. In multivariable analysis, AZA maintenance yielded significantly improved EFS ( p  = 0.019) and OS ( p  = 0.011). Outcomes differed according to regimen intensity. For reduced-intensity transplant, EFS ( p  = 0.004) and OS ( p  = 0.004) were significantly improved and equivalent to myeloablative transplant. A significant benefit following myeloablative transplant was not observed. Within the limitation of its retrospective nature, this study suggests that AZA maintenance improves outcomes following reduced-intensity HCT, comparable to myeloablative HCT.

Despite significant progress in diagnostics and disease management during the past decades, human immunodeficiency virus (HIV) infections are still responsible for nearly 1 million deaths every year, mostly in resource-limited settings. Thus, novel, accurate and cost-effective tools for viral load monitoring become crucial to allow specific diagnostics and the effective monitoring of the associated antiviral therapies. Herein, we report an effective combination of a (1) padlock probe (PLP)-mediated rolling circle amplification (RCA) bioassay and an (2) agarose bead-based microfluidic device for the affinity chromatography-based capture and detection of RCA products (RCPs) pre-labelled simultaneously with biotin and an organic fluorophore. This method allowed the efficient capture of ~1 μm-sized RCPs followed by their quantification either as discrete signals or an average fluorescence signal, thus being compatible with both high-resolution imaging for maximum sensitivity as well as simpler optical detection setups. A limit of detection < 30 fM was obtained for HIV-1 synthetic target with just a single round of RCA, comparable to recently reported procedures requiring technically complex amplification strategies such as hyperbranching and/or enzymatic digestion/amplification. Furthermore, targeting a set of five conserved regions in the HIV-1 gag gene, the method could specifically detect HIV-1 in 293T cell culture supernatants, as well as a set of 11 HIV-1 NIH reference samples with four different subtypes. The reported method provides simplicity of operation, unique versatility of signal transduction (i.e. average or discrete signals), and potential coupling with previously reported miniaturized photodetectors. These combined features hold promise for bringing RCA-based molecular diagnostics closer to the point-of-care., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Conflicting evidence exists regarding the importance of routine abdominal ultrasound (US) with hepatic and splenic fine needle aspiration (FNA) cytology during staging of canine mast cell tumours (MCT). The objective of this study was to correlate ultrasonographic and cytologic findings in dogs with strictly defined high-risk MCTs and to determine the influence on outcome. Our hypothesis was that US poorly predicts visceral metastasis in high-risk MCTs and that early metastasis is associated with improved outcome when compared to overt metastasis. US of liver and spleen correlated to cytologic results, categorized as no metastasis, early metastasis or overt metastasis. Of 82 dogs prospectively enrolled, 18% had early visceral metastasis and 7% had overt metastasis on cytology; 67% with visceral metastasis had regional LN metastasis. US was a poor predictor of metastasis with sensitivity, specificity, positive predictive value and negative predictive value for the spleen of 67%, 68%, 21% and 94%, respectively and for the liver of 29%, 93%, 56% and 82%, respectively. Median time to progression (TTP) for dogs with no metastasis, early metastasis and overt metastasis was not reached, 305 and 69 days, respectively (P < .001). Median survival time (MST) for the 3 groups were not reached, 322 and 81 days, respectively (P < .001). High Patnaik or Kiupel grade, early metastasis, overt metastasis and adequate local control were significantly associated with outcome. Early visceral metastasis was associated with poorer outcome compared to dogs without metastasis, however, a subset of dogs experienced long-term control., (© 2020 John Wiley & Sons Ltd.)

Purpose: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes., Experimental Design: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation., Results: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity., Conclusions: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment., (©2020 American Association for Cancer Research.)

Thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-SCT) can pose significant problems in management of patients. Eltrombopag is a small-molecule thrombopoietin receptor agonist that has been approved for use in immune thrombocytopenic purpura and aplastic anemia; but its use after allo-SCT is limited. Between 2014 and 2017, we treated 13 patients with eltrombopag for poor platelet engraftment without evidence of relapse at the time of initiation, including 6 patients with primary platelet engraftment failure and 7 with secondary platelet engraftment failure. Eltrombopag was started at an initial dose of 25 or 50 mg per day, and dose adjustments were made in accordance with the manufacturer's recommendation. The cumulative incidence of platelet recovery to ≥50,000/μL without the need for transfusion for at least 7 days was defined as response. The overall response rate was 62% (n = 8). Of the 6 patients with primary isolated platelet failure, 3 (50%) responded, and of the 7 patients with secondary platelet failure, 5 (71%) responded. The median time to response was 33 days (range, 11 to 68 days). In addition, no significant differences in platelet recovery were noted in patients with adequate and decreased bone marrow megakaryocytic reserve (60% and 67%, respectively). Although eltrombopag was well tolerated, and no patient discontinued treatment because of adverse events, only 3 patients were alive at the end of the observation period, with relapse and graft-versus-host disease accounting for majority of the deaths. This suggested that despite the relatively good overall response rate to eltrombopag, inadequate platelet engraftment is a harbinger of poor outcome in allo-SCT., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Among autoimmune diseases, systemic lupus erythematosus (SLE) patients have a unique predisposition to develop infections, which represents one of their main causes of morbidity and mortality. Many infections occur at disease diagnosis in the absence of immunosuppressive therapy, suggesting that the immunological abnormalities in SLE patients might be fundamental for the development of this complication. The aim of this study was to address the main clinical and immunological features associated with the development of infection and to create and validate a compound clinical-immunological infection predictive index in a cohort of SLE patients. We included 55 SLE patients with < 5 years since diagnosis. The clinical and immunological features were evaluated periodically and patients were followed-up during 1 year, searching for the development of infection. Immunophenotyping was performed by multiparametric flow cytometry and neutrophil extracellular traps (NETs) were assessed by confocal microscopy. Eighteen patients (32.7%) presented 19 infectious events, 5 (26.3%) were severe. For the construction of the index, we performed a logistic regression analysis and the cutoff points were determined with ROC curves. Increased numbers of peripheral Th17 cells, B cell lymphopenia, and lower TLR2 expression in monocytes, as well as the use of cyclophosphamide were the major risk factors for the development of infection and thus were included in the index. Besides, patients that developed infection were characterized by increased numbers of low-density granulocytes (LDGs) and higher expression of LL-37 in NETs upon infection. Finally, we validated the index retrospectively in a nested case-control study. A score >1.5 points was able to predict infection in the following year (AUC = 0.97; LR- = 0.001, specificity 100%, P = 0.0003). Our index encompasses novel immunological features able to prospectively predict the risk of infection in SLE patients.

Periostin is a secreted matricellular protein that primarily interacts with type I collagen and fibronectin extracellular matrix proteins, and is widely distributed in tissues rich in collagen-rich connective tissues, including the periodontal ligament. Its expression in these tissues is especially regulated by mechanical load. While the expression and regulation of periostin in the teeth of murine models and cell lines is well known, its presence in human teeth is poorly documented. Here we update and summarize the available data on the distribution of periostin in the human periodontal ligament, gingiva and dental pulp.

[This corrects the article DOI: 10.18632/oncotarget.11785.].

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while β-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and β-catenin inhibitors. Moreover, these cells regained β-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. This finding shines a light on ways to repurpose FDA-approved drugs to augment T cell-based cancer immunotherapies.

Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy.

Bioprospecting for novel microalgal strains is key to improving the feasibility of microalgae-derived biodiesel production. Tetraselmis sp. CTP4 (Chlorophyta, Chlorodendrophyceae) was isolated using fluorescence activated cell sorting (FACS) in order to screen novel lipid-rich microalgae. CTP4 is a robust, euryhaline strain able to grow in seawater growth medium as well as in non-sterile urban wastewater. Because of its large cell size (9-22 μm), CTP4 settles down after a six-hour sedimentation step. This leads to a medium removal efficiency of 80%, allowing a significant decrease of biomass dewatering costs. Using a two-stage system, a 3-fold increase in lipid content (up to 33% of DW) and a 2-fold enhancement in lipid productivity (up to 52.1 mg L -1 d -1 ) were observed upon exposure to nutrient depletion for 7 days. The biodiesel synthesized from the lipids of CTP4 contained high levels of oleic acid (25.67% of total fatty acids content) and minor amounts of polyunsaturated fatty acids with ≥4 double bonds (<1%). As a result, this biofuel complies with most of the European (EN14214) and American (ASTM D6751) specifications, which commonly used microalgal feedstocks are usually unable to meet. In conclusion, Tetraselmis sp. CTP4 displays promising features as feedstock with lower downstream processing costs for biomass dewatering and biodiesel refining.

Redirection of T cells to target and destroy tumors has become an important clinical tool and major area of research in tumor immunology. Here we present a novel, nanoparticle-based approach to selectively bind antigen-specific cytotoxic T cells (CTL) and redirect them to kill tumors, termed ATR (Antigen-specific T cell Redirectors). ATR were generated by decorating nanoparticles with both an antigen-specific T cell binding moiety, either peptide loaded MHC-Ig dimer or clonotypic anti-TCR antibody, and a model tumor cell binding moiety, anti-CD19 antibody to engage CD19+ tumor cells. ATR stably bind tumor cells and CTL in a dose dependent fashion and stimulate antigen-specific conjugate formation between those cells. ATR induced redirected lysis of tumor cells in vitro, as demonstrated by 51Cr-release killing. In vivo ATR administration led to reduced tumor growth in a SCID/beige human lymphoma treatment model. In summary, ATR represent a novel, nanoparticle based approach for redirecting antigen-specific CTL to kill tumors.

Optimal chemotherapy protocols for high-risk mast cell tumours (MCTs) are unknown. The purpose of this study was to determine the tolerability and toxicity profile of a rapidly escalating vinblastine and prednisolone protocol (VPP) in which 3.00 mg/m 2 was administered once 7 days apart: at day 14 and at day 21. Dogs with chemotherapy-naïve MCTs presenting to the Oncology Service of a single institution were prospectively enrolled to receive escalating vinblastine, and haematology and a standardised quality-of-life questionnaire were assessed prior to each dosage. Thirty-four dogs were included: 30 with microscopic disease treated with adequate local therapy and four with macroscopic disease. Of 220 doses of vinblastine administered, 4% were associated with grade 3 and 4 toxicity. A total of 70% of dogs tolerated 3.00 mg/m 2 given 7 days apart at day 14 and 21, although 29% of dogs developed dose-limiting toxicities and 8% discontinued the protocol due to toxicity. In conclusion, VPP was well-tolerated overall, although prior to further dose intensity optimisation, it is important to determine if dose intensity is linked to outcome in canine MCT to avoid unwarranted toxicity.

Carotenoids are a wide group of lipophylic isoprenoids synthesized by all photosynthetic organisms and also by some non-photosynthetic bacteria and fungi. Animals, which cannot synthesize carotenoids de novo, must include them in their diet to fulfil essential provitamin, antioxidant, or colouring requirements. Carotenoids are indispensable in light harvesting and energy transfer during photosynthesis and in the protection of the photosynthetic apparatus against photooxidative damage. In this review, we outline the factors inducing carotenoid accumulation in microalgae, the knowledge acquired on the metabolic pathways responsible for their biosynthesis, and the recent achievements in the genetic engineering of this pathway. Despite the considerable progress achieved in understanding and engineering algal carotenogenesis, many aspects remain to be elucidated. The increasing number of sequenced microalgal genomes and the data generated by high-throughput technologies will enable a better understanding of carotenoid biosynthesis in microalgae. Moreover, the growing number of industrial microalgal species genetically modified will allow the production of novel strains with enhanced carotenoid contents.

Adoptive immunotherapy (AIT) can mediate durable regression of cancer, but widespread adoption of AIT is limited by the cost and complexity of generating tumor-specific T cells. Here we develop an Enrichment + Expansion strategy using paramagnetic, nanoscale artificial antigen presenting cells (aAPC) to rapidly expand tumor-specific T cells from rare naïve precursors and predicted neo-epitope responses. Nano-aAPC are capable of enriching rare tumor-specific T cells in a magnetic column and subsequently activating them to induce proliferation. Enrichment + Expansion resulted in greater than 1000-fold expansion of both mouse and human tumor-specific T cells in 1 week, with nano-aAPC based enrichment conferring a proliferation advantage during both in vitro culture and after adoptive transfer in vivo. Robust T cell responses were seen not only for shared tumor antigens, but also for computationally predicted neo-epitopes. Streamlining the rapid generation of large numbers of tumor-specific T cells in a cost-effective fashion through Enrichment + Expansion can be a powerful tool for immunotherapy., Competing Interests: COMPETING FINANCIAL INTERESTS: Under a licensing agreement between NexImmune and the Johns Hopkins University, JPS and MO are entitled to a share of royalty received by the University on sales of products derived from this article. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

The complement system is an essential component of the immune system. It is a highly integrative system and has a number of functions, including host defense, removal of injured cells and debris, modulation of metabolic and regenerative processes, and regulation of adaptive immunity. Complement is activated via different pathways and it is regulated tightly by several mechanisms to prevent host injury. Imbalance between complement activation and regulation can manifest in disease and injury to self. This article provides an outline of complement activation pathways, regulatory mechanisms, and normal physiologic functions of the system., (Published by Elsevier Inc.)

Purpose: Artificial antigen-presenting cells, aAPC, have successfully been used to stimulate antigen-specific T-cell responses in vitro as well as in vivo. Although aAPC compare favorably with autologous dendritic cells in vitro, their effect in vivo might be diminished through rapid clearance by macrophages. Therefore, to prevent uptake and minimize clearance of aAPC by macrophages, thereby increasing in vivo functionality, we investigated the efficiency of "don't eat me" three-signal aAPC compared with classical two-signal aAPC., Experimental Design: To generate "don't eat me" aAPC, CD47 was additionally immobilized onto classical aAPC (aAPC(CD47+)). aAPC and aAPC(CD47+) were analyzed in in vitro human primary T-cell and macrophage cocultures. In vivo efficiency was compared in a NOD/SCID T-cell proliferation and a B16-SIY melanoma model., Results: This study demonstrates that aAPC(CD47+) in coculture with human macrophages show a CD47 concentration-dependent inhibition of phagocytosis, whereas their ability to generate and expand antigen-specific T cells was not affected. Furthermore, aAPC(CD47+)-generated T cells displayed equivalent killing abilities and polyfunctionality when compared with aAPC-generated T cells. In addition, in vivo studies demonstrated an enhanced stimulatory capacity and tumor inhibition of aAPC(CD47+) over normal aAPC in conjunction with diverging biodistribution in different organs., Conclusions: Our data for the first time show that aAPC functionalized with CD47 maintain their stimulatory capacity in vitro and demonstrate enhanced in vivo efficiency. Thus, these next-generation aAPC(CD47+) have a unique potential to enhance the application of the aAPC technology for future immunotherapy approaches., (©2015 American Association for Cancer Research.)

Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT). Using this approach, tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available.

Ionic channels play key roles in the sensory cells, such as transducing specific stimuli into electrical signals. The acid-sensing ion channel (ASIC) family is voltage-insensitive, amiloride-sensitive, proton-gated cation channels involved in several sensory functions. ASIC2, in particular, has a dual function as mechano- and chemo-sensor. In this study, we explored the possible role of zebrafish ASIC2 in olfaction. RT-PCR, Western blot, chromogenic in situ hybridization and immunohistochemistry, as well as ultrastructural analysis, were performed on the olfactory rosette of adult zebrafish. ASIC2 mRNA and protein were detected in homogenates of olfactory rosettes. Specific ASIC2 hybridization was observed in the luminal pole of the non-sensory epithelium, especially in the cilia basal bodies, and immunoreactivity for ASIC2 was restricted to the cilia of the non-sensory cells where it was co-localized with the cilia marker tubulin. ASIC2 expression was always absent in the olfactory cells. These findings demonstrate for the first time the expression of ASIC2 in the olfactory epithelium of adult zebrafish and suggest that it is not involved in olfaction. Since the cilium sense and transduce mechanical and chemical stimuli, ASIC2 expression in this location might be related to detection of aquatic environment pH variations or to detection of water movement through the nasal cavity.

A new thermoplastic polymer for orthodontic applications was obtained and extruded into wires with round and rectangular cross sections. We evaluated the potential of new aesthetic archwire: tensile, three point bending, friction and stress relaxation behaviour, and formability characteristics were assessed. Stresses delivered were generally slightly lower than typical beta-titanium and nickel-titanium archwires. The polymer wire has good instantaneous mechanical properties; tensile stress decayed about 2% over 2h depending on the initial stress relaxation for up to 120h. High formability allowed shape bending similar to that associated with stainless steel wires. The friction coefficients were lower than the metallic conventional archwires improving the slipping with the brackets. This new polymer could be a good candidate for aesthetic orthodontic archwires., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Light-emitting diodes (LEDs) will become one of the world's most important light sources and their integration in microalgal production systems (photobioreactors) needs to be considered. LEDs can improve the quality and quantity of microalgal biomass when applied during specific growth phases. However, microalgae need a balanced mix of wavelengths for normal growth, and respond to light differently according to the pigments acquired or lost during their evolutionary history. This review highlights recently published results on the effect of LEDs on microalgal physiology and biochemistry and how this knowledge can be applied in selecting different LEDs with specific technical properties for regulating biomass production by microalgae belonging to diverse taxonomic groups., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The hydrolysis of seaweed polysaccharides is the rate limiting step in anaerobic digestion (AD) of seaweeds. Seven different microbial inocula and a mixture of these (inoculum 8) were therefore compared in triplicate, each grown over four weeks in static culture for the ability to degrade Laminaria hyperborea seaweed and produce methane through AD., Results: All the inocula could degrade L. hyperborea and produce methane to some extent. However, an inoculum of slurry from a human sewage anaerobic digester, one of rumen contents from seaweed-eating North Ronaldsay sheep and inoculum 8 used most seaweed volatile solids (VS) (means ranged between 59 and 68% used), suggesting that these each had efficient seaweed polysaccharide digesting bacteria. The human sewage inoculum, an inoculum of anaerobic marine mud mixed with rotting seaweed and inoculum 8 all developed to give higher volumes of methane (means between 41 and 62.5 ml g-1 of seaweed VS by week four) ,compared to other inocula (means between 3.5 and 27.5 ml g-1 VS). Inoculum 8 also gave the highest acetate production (6.5 mmol g-1 VS) in a single-stage fermenter AD system and produced most methane (8.4 mL mmol acetate-1) in phase II of a two-stage AD system., Conclusions: Overall inoculum 8 was found to be the most efficient inoculum for AD of seaweed. The study therefore showed that selection and inclusion of efficient polysaccharide hydrolysing bacteria and methanogenic archaea in an inoculum offer increased methane productivity in AD of L. hyperborea. This inoculum will now being tested in larger scale (10L) continuously stirred reactors optimised for feed rate and retention time to determine maximum methane production under single-stage and two-stage AD systems.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells due to a mutation in the PIG-A gene leading to a deficiency of GPI-anchored proteins. Lack of two specific GPI-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that result in both intravascular and extravascular hemolysis. Free hemoglobin leads to nitric oxide depletion that mediates the pathophysiology of some of the common clinical signs of PNH. Clinical symptoms of PNH include evidence of hemolytic anemia, bone marrow failure, smooth muscle dystonias and thromboses. Treatment options for patients with PNH include bone marrow transplantation, a therapy associated with high morbidity and mortality, or treatment with the complement inhibitor eculizumab. Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life (QoL) of patients.

Esophageal duplication cysts are infrequent anomalies of the gastrointestinal tract that are predominantly found in children. The conventional surgical approach for removal of these cysts is an open surgery one with a posterolateral thoracotomy incision. However, more recently, these cysts have been excised via video-assisted thoracoscopic surgery (VATS). In this article, we present 2 pediatric patients treated with successful excision of an esophageal duplication cyst via robotic-assisted thoracoscopic surgery (RATS) using the da Vinci surgical system. With robotic technology, precise dissection and complete resection of the thoracic mass was achieved without violating the esophageal mucosa. There were no complications, and the patients did not require placement of a postoperative chest tube. Pathological examination of the mass was consistent with an esophageal (foregut) duplication cyst in both cases.

Introduction: Vesicoureteral reflux (VUR), a complication after kidney transplantation, may be caused by recurrent urinary tract infections evaluating in life-threatening pyelonephritis and urosepsis. Open surgical correction is the standard treatment despite its morbidity. However, minimally invasive approaches are available., Materials and Methods: Our study group describes seven patients with functioning kidney grafts and a diagnosis of VUR associated with recurrent urinary tract infections. The procedure was performed under antibiotic prophylaxis and spinal anesthesia. An endoscopic injection of 1 mL of biomaterial (copolymer of dextranomer and hyalurunic acid) was administered into the ureteral neo-orifice following the Sting technique. The catheter was removed within 24 hours in all cases., Results: Between June 2009 and January 2010, nine procedures were performed in seven patients. Two patients experienced self-limiting post-surgical episodes of hematuria that did not need urologic manipulation. There were no episodes of retention, ureteral obstruction, or urinary infections. One patient required a reinjection 5 months later as a result of clinical failure. Apart from this one case, the other patients showed improvements with no infectious complications., Conclusions: Endoscopic correction with VUR seems to be a reliable and safe option as a first treatment for the transplant patient. More cases are required in order to improve the learning curve and, therefore, the success rate. Closer monitoring is needed to evaluate the efficiency of the copolymer, the evolution of the reflux, and the possible long-term complications in this sort of patients., (Copyright © 2010. Published by Elsevier Inc.)

Background: The complement cascade forms part of the initial innate response to pathogens in the airway. Complement activation is important in the maintenance of host homeostasis, but excessive and uncontrolled activation may lead to inflammation and disease. The role of the complement pathway in the innate response in chronic rhinosinusitis (CRS) is poorly characterized Methods: Sinus mucosa biopsy specimens from the anterior ethmoid or uncinate process of patients with allergic fungal rhinosinusitis (AFRS), CRS without NPs (CRS-NPs), and controls were harvested and gene and protein expression of C3, factor B (fB), C5, and C7 complement proteins were analyzed using quantitative polymerase chain reaction and immunohistochemical techniques., Results: fB, C3, and C5 gene expression were increased in both AFRS and CRS-NPs compared with controls (p < 0.05). Transcriptional activity for the terminal pathway protein C7 was not significantly increased when compared with controls, with C7 levels actually reduced in AFRS patients when compared with controls. Immunohistochemistry studies showed the presence of C3 and fB on the mucosal surface and in submucosa of both AFRS and CRS-NPs, but not normal controls. Terminal pathway protein C9 was not found in our specimens., Conclusion: Both AFRS and CRS-NPs display up-regulation of the complement pathway, in particular, the alternative pathway (fB) and common pathways (C3 and C5). Enhanced innate responses as shown by alterations in complement components may play a pivotal role in the inflammatory response noted in CRS and provide potential therapeutic targets in the future.

Rationale: Donor brain death (BD) is an unavoidable occurrence in heart transplantation and results in profound physiological derangements that render the heart more susceptible to ischemia/reperfusion injury in the recipient and likely has negative long-term consequences to allograft survival., Objective: We developed a novel mouse model of BD and investigated the role of complement in BD-induced myocardial inflammation and injury., Methods and Results: BD was induced by inflation of a balloon catheter in the cranial cavity. BD in wild-type mice resulted in a significant increase in serum concentrations of the complement activation product complement component (C)3a, and immunohistochemical analysis of heart sections demonstrated C3 deposition on the vascular endothelium and surrounding myocytes. Following induction of BD in complement (C3)-deficient mice, cardiac troponin levels, and histological evidence of injury were significantly reduced compared to wild-type mice. C3 deficiency was also associated with reduced myocardial leukocyte infiltration and reduced or absent expression of P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-alpha, and interleukin-1beta., Conclusions: These data indicate an important role for complement in BD-induced inflammation and injury and suggest that a complement inhibitory strategy applied to the donor (in addition to the recipient) may provide graft protection.

In green algae, the final step of the plastidial methylerythritol phosphate (MEP) pathway is catalyzed by 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR; EC: 1.17.1.2), an enzyme proposed to play a key role in the regulation of isoprenoid biosynthesis. Here we report the isolation and functional characterization of a 1959-bp Dunaliella salina HDR (DsHDR) cDNA encoding a deduced polypeptide of 474 amino acid residues. Phylogenetic analysis implied a cyanobacterial origin for plant and algal HDR genes. Steady-state DsHDR transcript levels were higher in D. salina cells submitted to nutritional depletion, high salt and/or high light, suggesting that DsHDR may respond to the same environmental cues as genes involved in carotenoid biosynthesis.

Membrane complement inhibitors (CD46, CD55 and CD59) are upregulated in some human cancers indicating that they play a role in immune evasion. We investigated complement inhibitor expression in bladder cancer and examined the hypothesis that selective pressure of an antibody response (anti-MUC1) results in the upregulated expression of complement inhibitors on tumor cells. Paired samples of tumor and normal tissue from 22 bladder cancer patients were analyzed for expression of MUC1, CD46, CD55 and CD59, and matched serum samples analyzed for anti-MUC1 IgM and IgG levels. Relationships between anti-MUC1 antibody levels and complement inhibitor expression were investigated. MUC1 mRNA was upregulated in 86% of tumor samples. CD46 was upregulated in 77%, CD55 in 55% and CD59 in 59% of tumors. Low titer anti-MUC1 IgM was detected in normal human sera, but was elevated in 41% of the bladder cancer patients. Anti-MUC1 IgG was virtually absent from normal sera, but present in 32% of the cancer patients. There was a direct relationship between anti-MUC1 antibody titer and expression level of complement inhibitors. Analysis of the correlation of each antibody with the expression of each complement inhibitor by Spearman's rank test revealed a strong correlation between both anti-MUC1 IgM and IgG levels and increased expression of CD46 and CD55, and combined anti-MUC1 IgM/IgG levels correlated with increased expression of all 3 complement inhibitors. In conclusion, the data demonstrate upregulated complement inhibitor expression and the presence of an anti-MUC1 antibody response in bladder cancer patients and support the hypothesis of antibody-mediated immune selection., (Copyright 2008 Wiley-Liss, Inc.)